Polymer particles

ABSTRACT

Polymer particle embolics and methods of making same are described. The particle embolics can be used as embolization agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/693,077, filed Nov. 22, 2019, which is a continuation of U.S. patentapplication Ser. No. 16/147,225, filed Sep. 28, 2018, now U.S. Pat. No.10,519,264, which is a continuation of U.S. patent application Ser. No.15/604,529, filed May 24, 2014, now U.S. Pat. No. 10,118,980, which is acontinuation of U.S. patent application Ser. No. 14/536,394, filed Nov.7, 2014, now U.S. Pat. No. 9,688,788, which claims the benefit of U.S.Provisional Patent Application No. 61/902,020, filed Nov. 8, 2013, theentire disclosure each of which is incorporated herein by reference.

FIELD

Polymer particles for the occlusion of vascular sites and cavitieswithin the body, such as the embolization of vascularized tumors orarteriovenous malformations are described.

SUMMARY

Described herein generally are particles including a polyether andoptionally one or more monomers. These polymers can be used for/inembolization. The polymer particles are compressible for ease ofdelivery. Further, in some embodiments, the polymer particles are stablein/at physiological conditions. In some embodiments, the particles canbe loaded or coated with a drug(s) or active agent(s).

Polymer particles as described can comprise: at least one polyetherincluding at least two functional groups and optionally at least onemonomer. Particles as described herein can have various sizes dependingon a particular use, but generally can have diameters less than about1,200 μm.

Further, in other embodiments, polymer particles are describedcomprising: at least one derivatized poly(ethylene glycol) macromer,poly(propylene glycol) macromer, poly(tetramethylene oxide) macromer, ora combination thereof at a concentration of between about 15% w/w andabout 50% w/w; and at least one monomer that is not n-isopropylacrylamide.

The polymer particles can have an average diameter between about 40 μmand about 1,200 μm.

The polymer particles can further include at least one monomer. The atleast one monomer can include a functional group. The functional groupcan be an acrylate, acrylamide, methacrylate, or methacrylamide.Further, the at least one monomer can be glycerol monomethacrylate,amino ethyl methacrylate, 3-sulfopropyl acrylate, amino propylmethacrylate, or a combination thereof.

In one embodiment, the at least one monomer is glycerol monomethacrylateat a concentration of about 68% w/w. In another embodiment, the at leastone monomer is 3-sulfopropyl acrylate at a concentration of about 59%w/w. In still another embodiment, the at least one monomer is aminopropyl methacrylate at a concentration of about 1% w/w. In yet anotherembodiment, the at least one monomer is amino ethyl methacrylate at aconcentration of about 3% w/w.

In some embodiments, the at least one derivatized poly(ethylene glycol)macromer can be poly(ethylene glycol) diacrylamide, poly(ethyleneglycol) diacrylate, poly(ethylene glycol) dimethacrylate, poly(ethyleneglycol) dimethacrylamide, or a combination thereof.

Methods of making polymer particles as described herein are alsodisclosed. These methods can comprise: reacting an aqueous basedprepolymer solution including at least one derivatized polyethermacromer and an initiator in an oil to form polymer particles; whereinsaid polymer particle has a diameter less than about 1,200 μm.

In some embodiments of the methods, the oil is a mineral oil. In otherembodiments of the methods, the initiator is ammonium persulfate,tetramethylethylene diamine, or a combination thereof.

In embodiments of the methods and particles described herein, thecompositions and particles do not include n-isopropyl acrylamide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a plot of average drug loading of particles chargedwith doxorubicin or irinotecan.

FIG. 2 illustrates a plot of average drug elution from particles at 22hours after in situ.

FIG. 3 illustrates a plot of particle compressibility at 30%deformation.

FIG. 4 illustrates another plot of particle compressibility at 30%deformation.

FIG. 5 illustrates a plot of particle time in suspension.

FIG. 6 illustrates a plot of drug loaded particle time in suspension.

DETAILED DESCRIPTION

Described herein generally are particles made of polymer materialincluding a reaction product of at least one polyether macromer,optionally at least one monomer, optionally at least one multifunctionalcrosslinker, and optionally at least one initiator. The particles can bereferred to herein as being microparticles, microspheres, microbeads,spheres, microembolis, embolics, and the like. The particles can havediameters less than about 1,200 μm. The particles can also becompressible, biostable, and/or durable for ease of delivery.

The particles can be formed from a prepolymer solution or mixturecomprising: (i) one or more polyether macromers that contain at leasttwo functional groups amenable to polymerization, (ii) optionally one ormore monomers, and (iii) optionally one or more multifunctionalcrosslinkers. In some embodiments, a polymerization initiator may beutilized.

In one embodiment, the macromer includes a plurality of functionalgroups suitable or amenable to polymerization. In some embodiments, themacromer can be linear. In other embodiments, the macromer can have oneor more branches. In still other embodiments, the macromer can be anethylenically unsaturated macromer. Macromers can include polyethers.Polyether macromers can include linear or branched poly(ethyleneglycol), poly(propylene glycol), poly(tetramethylene oxide), derivativesthereof, or combinations thereof.

Macromers described herein can have molecular weights of about 200grams/mole, 400 grams/mole, 600 grams/mole, 800 grams/mole, 1,000grams/mole, 2,000 grams/mole, 3,000 grams/mole, 4,000 grams/mole, 5,000grams/mole, 10,000 grams/mole, 15,000 grams/mole, 20,000 grams/mole,25,000 grams/mole, 30,000 grams/mole, 35,000 grams/mole, between about200 grams/mole and about 35,000 grams/mole, between about 200 grams/moleand about 30,000 grams/mole, between about 1,000 grams/mole and about15,000 grams/mole, at least about 200 grams/mole, at most about 30,000g/mole, or at most about 35,000 grams/mole. In one embodiment, macromerscan have a molecular weight of about 10,000 g/mole.

Derivatives of these polyethers can be prepared to render them amenableto polymerization. While any type of chemistry can be utilized, forexample nucleophile/N-hydroxysuccinimide esters, nucleophile/halide,vinyl sulfone/acrylate or maleimide/acrylate; a preferred chemistry isfree radical polymerization. As such, polyethers with a plurality ofethylenically unsaturated groups, such as acrylate, acrylamide,methacrylate, methacrylamide, and vinyl, can be used. In one embodiment,a polyether macromer can be poly(ethylene glycol) diacrylamide with amolecular weight of about 10,000 g/mole.

In another embodiment the macromer is poly(ethylene glycol)diacrylamide, poly(ethylene glycol) diacrylate, poly(ethylene glycol)dimethacrylate, poly(ethylene glycol) dimethacrylamide, derivativesthereof, or combinations thereof.

Macromers can be included at a concentration in the solution of about 0%w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5%w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10%w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w,about 20% w/w, about 35% w/w, about 30% w/w, about 35% w/w, about 40%w/w, about 45% w/w, about 50% w/w, about 60% w/w, about 70% w/w, betweenabout 5% w/w and about 10% w/w, between about 5% w/w and about 20% w/w,between about 5% w/w and about 25% w/w, between about 5% w/w and about15% w/w, between about 6% w/w and about 8% w/w, or between about 14% w/wand about 16% w/w. In some embodiments, a macromer need not be used.

In one embodiment, the macromer can be included at a concentration ofabout 7% w/w in the solution.

In one embodiment, the macromer can be included at a concentration ofabout 15% w/w in the solution.

In some embodiments, if one of the monomer(s) and/or macromers(s) is asolid, a solvent can be used to form a solution from which the particlesfor use as embolics can be prepared. If liquid monomers and macromersare utilized, a solvent may not be required. In some embodiments, evenwhen using liquid monomers and/or macromers, a solvent may still beused. Solvents may include any liquid that can dissolve or substantiallydissolve a polyether macromer, monomers, multifunctional crosslinkers,and/or initiators. Any aqueous or organic solvent may be used thatdissolves the desired monomer(s), macromer(s), multifunctionalcrosslinker(s) and/or polymerization initiators. In one embodiment, thesolvent can be water. Additionally, solutes, e.g. sodium chloride, maybe added to the solvent to increase the rate of polymerization. Solventconcentration can be varied to alter the compressibility of the embolicparticle, allowing for delivery through a catheter of smaller innerdiameter than the diameter of the particle.

Solvent concentrations can be about 25% w/w, about 35% w/w, about 45%w/w, about 55% w/w, about 65% w/w, about 75% w/w, about 85% w/w, about95% w/w, between about 40% w/w and about 80% w/w, between about 30% w/wand about 90% w/w, or between about 50% w/w and about 70% w/w of thesolution. In one embodiment, the solvent concentration can be about 50%w/w, about 51% w/w, about 52% w/w, about 53% w/w, about 54% w/w, about55% w/w, about 56% w/w, about 57% w/w, about 58% w/w, about 59% w/w, orabout 60% w/w. In another embodiment, the solvent concentration can beabout 65% w/w, about 66% w/w, about 67% w/w, about 68% w/w, about 69%w/w, about 70% w/w, about 71% w/w, about 72% w/w, about 73% w/w, about74% w/w, or about 75% w/w.

In one embodiment, the solvent concentration can be about 57% w/w.

In one embodiment, the solvent concentration can be about 70% w/w.

In one embodiment, the solvent concentration can be about 75% w/w.

In general, monomers can contain moieties such as acrylate, acrylamide,methacrylate, methacrylamide or other moieties amenable topolymerization. In one embodiment, the polymer particles are comprisedof one or more macromers combined with one or more monomers.

Optionally, one or more monomers can be added to the polyether macromerto impart desired chemical and/or mechanical properties to the polymerparticle. If the binding of positively charged drugs or other materialsis desired, monomers with negatively charged moieties, e.g. carboxylicacids, can be polymerized into the particles. Acidic unsaturatedmonomers can include, but are not limited to, acrylic acid, methacrylicacid, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, derivativesthereof, combinations thereof, and salts thereof. If the binding ofnegatively charged drugs is desired, monomers with positively chargedmoieties, e.g. amines, can be polymerized into the particles. Basicmonomers can include amino ethyl methacrylate, 2-amino ethylmethacrylate, amino propyl methacrylamide, derivatives thereof,combinations thereof, and salts thereof.

Monomers including positive or negative moieties can be present insolution at concentrations of about 0.5% w/w, about 1% w/w, about 2%w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7%w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 15% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w,about 30% w/w, about 40% w/w, about 50% w/w, about 55% w/w, about 60%w/w, about 65% w/w, about 70% w/w, about 80% w/w, between about 1% w/wand about 10% w/w, between about 1% w/w and about 5% w/w, between about15% w/w and about 35% w/w, or between about 20% w/w and about 30% w/w.

In one embodiment, a monomer(s) including charged moieties can beincluded at a concentration of about 14% w/w in the solution.

In one embodiment, a monomer(s) including charged moieties can beincluded at a concentration of about 24% w/w in the solution.

In one embodiment, 2-amino ethyl methacrylate can be included at aconcentration of about 0.7% w/w in the solution.

In one embodiment, amino propyl methacrylamide can be included at aconcentration of about 0.5% w/w in the solution.

In one embodiment, the monomer is not n-isopropyl acrylamide. In otherembodiments, the polymer particles described herein do not includen-isopropyl acrylamide.

If desired, uncharged, reactive moieties can be introduced into theparticles. For example, hydroxyl groups can be introduced into theparticles with the addition of 2-hydroxyethyl acrylate, 2-hydroxyethylmethacrylate, glycerol monomethacrylate, glycerol monoacrylate, sorbitolmonomethacrylate, sorbitol monoacrylate, a carbohydrate similar tosorbitol and amenable to polymerization, derivatives thereof, orcombinations thereof. Alternatively, uncharged, relatively un-reactivemoieties can be introduced into the particles. For example, acrylamide,methacrylamide, methyl methacrylate, derivatives thereof, orcombinations thereof can be added to the polyether macromer. In someembodiments, the monomer(s) can be selected to vary the number ofhydroxyl groups in the polymeric particles to enable the particles toremain suspended in radiopaque contrast solution used in the preparationof the particle for clinical use.

Such uncharged moieties if included can be present in the final particle(not including solvents, initiators, and salts) at about 0% w/w, about10% w/w, about 20% w/w, about 30% w/w, about 40% w/w, about 50% w/w,about 60% w/w, about 61% w/w, about 62% w/w, about 63% w/w, about 64%w/w, about 65% w/w, about 66% w/w, about 67% w/w, about 68% w/w, about69% w/w, about 70% w/w, about 71% w/w, about 72% w/w, about 73% w/w,about 74% w/w, about 75% w/w, about 80% w/w, about 90% w/w, betweenabout 50% w/w and about 90% w/w, between about 60% w/w and about 70%w/w, between about 65% w/w and about 70% w/w, or between about 67% w/wand about 69% w/w.

In one embodiment, an uncharged moiety can be present at about 68% w/wof the final particle.

In one embodiment, the uncharged moiety can be glycerolmonomethacrylate.

Adding multifunctional crosslinkers containing more than one moietyamenable to polymerization can create a more cohesive hydrogel polymerby adding crosslinking to the molecular structure. In some embodimentsthe polymer particles are comprised of a macromer combined with one ormore multifunctional crosslinkers such as, but not limited to, glyceroldimethacrylate, glycerol diacrylate, sorbitol dimethacrylate, sorbitolacrylate, a derivatized carbohydrate similar to sorbitol, derivativesthereof, or combinations thereof. In a preferred embodiment themultifunctional crosslinker is N,N′-methylenebisacrylamide.

If used, a crosslinker can be present in the solution used to form theparticles at a concentration of about 0.1% w/w, about 0.25% w/w, about0.5% w/w, about 0.75% w/w, about 1.0% w/w, about 1.25% w/w, about 1.5%w/w, about 1.75% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5%w/w, about 6% w/w, about 7% w/w, about 10% w/w, about 20% w/w, about 25%w/w, about 30% w/w, between about 0% w/w and about 10% w/w, betweenabout 0% w/w and about 2% w/w, between about 0.5% w/w and about 1.5%w/w, between about 0.25% w/w and about 1.75% w/w, or between about 0.1%w/w and about 2% w/w.

In one embodiment, a crosslinker is not used.

In one embodiment, a crosslinker can be present at about 1% w/w.

In one embodiment, the crosslinker can be N,N′-methylenebisacrylamide.

Any amounts of macromer(s), monomer(s), and multifunctionalcrosslinker(s) can be used in the solution used to form the particlesthat allows for a desired particle. Total concentration of reactivecompounds or solids in the solution can be about 5% w/w, about 10% w/w,about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15%w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w,about 25% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about 33%w/w, about 34% w/w, about 35% w/w, about 36% w/w, about 37% w/w, about38% w/w, about 39% w/w, 40% w/w, about 50% w/w, about 60% w/w, about 70%w/w, between about 10% and 60%, between about 15% w/w and about 50% w/w,or between about 20% w/w and about 40% w/w.

In one embodiment, the total concentration of reactive compounds in thesolution can be about 20% w/w.

In one embodiment, the total concentration of reactive compounds in thesolution can be about 41% w/w.

In one embodiment, polymer particles can be prepared from monomershaving a single functional group and/or macromers having two or morefunctional groups suitable for polymerization. Functional groups caninclude those suitable to free radical polymerization, such as acrylate,acrylamide, methacrylate, and methacrylamide. Other polymerizationschemes can include, but are not limited tonucleophile/N-hydroxysuccinimide esters, nucleophile/halide, vinylsulfone/acrylate or maleimide/acrylate. Selection of the monomers isgoverned by the desired chemical and mechanical properties of theresulting particle.

Concentrations of macromers in the final desiccated particle productscan be at a concentration of about 10% w/w, about 20% w/w, about 21%w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, about 30% w/w,about 35% w/w, about 36% w/w, about 37% w/w, about 38% w/w, about 39%w/w, about 40% w/w, about 41% w/w, about 42% w/w, about 43% w/w, about44% w/w, about 45% w/w, about 50% w/w, about 60% w/w, about 70% w/w,about 80% w/w, between about 15% w/w and about 60% w/w, between about20% w/w and about 50% w/w, between about 25% w/w and about 45% w/w,between about 25% w/w and about 40% w/w, between about 35% w/w and about45% w/w, between about 37% w/w and about 43% w/w, between about 39% w/wand about 41% w/w, between about 25% w/w and about 35% w/w, betweenabout 26% w/w and about 30% w/w, or between about 27% w/w and about 29%w/w.

In one embodiment, the concentration of macromer(s) in the finaldesiccated particle products can be about 40% w/w.

In one embodiment, the concentration of macromer(s) in the finaldesiccated particle products can be about 27% w/w.

In one embodiment, poly(ethylene glycol) diacrylamide is present in thefinal desiccated particle products at about 40% w/w.

In one embodiment, poly(ethylene glycol) diacrylamide is present in thefinal desiccated particle products at about 27% w/w.

Concentrations of crosslinkers in the final desiccated particle productscan be about 0.1% w/w, about 0.25% w/w, about 0.5% w/w, about 0.75% w/w,about 1% w/w, about 1.25% w/w, about 1.5% w/w, about 1.75% w/w, about 2%w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7%w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 15% w/w, about 20%w/w, about 25% w/w, about 30% w/w, between about 0% w/w and about 5%w/w, between about 0% w/w and about 2% w/w, between about 0.5% w/w andabout 1.5% w/w, between about 0.25% w/w and about 1.75% w/w, or betweenabout 0.1% w/w and about 2% w/w.

In one embodiment, a crosslinker can be present in the final desiccatedparticle products at about 1% w/w.

In one embodiment, no crosslinker can be present in the final desiccatedparticle products.

In one embodiment, the crosslinker can be N,N′-methylenebisacrylamide.

Concentrations of one or more monomers in the final desiccated productscan be about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about30% w/w, about 40% w/w, about 50% w/w, about 55% w/w, about 60% w/w,about 61% w/w, about 62% w/w, about 63% w/w, about 64% w/w, about 65%w/w, about 66% w/w, about 67% w/w, about 68% w/w, about 69% w/w, about70% w/w, about 71% w/w, about 72% w/w, about 73% w/w, about 74% w/w,about 75% w/w, about 80% w/w, between about 50% w/w and 80% w/w, betweenabout 60% w/w and 70% w/w, between about 50% w/w and 80% w/w, betweenabout 50% w/w and 75% w/w, between about 55% w/w and about 65% w/w,between about 57% w/w and 63% w/w, between about 59% w/w and 61% w/w,between about 63% w/w and 73% w/w, between about 65% w/w and 71% w/w, orbetween about 67% w/w and 69% w/w.

In one embodiment, the concentration of one or more monomers in thefinal desiccated products can be about 72% w/w.

In one embodiment, the concentration of one or more monomers in thefinal desiccated products can be about 60% w/w.

In one embodiment, the one or more monomers can be glycerolmonomethacrylate and 2-amino ethyl methacrylate.

In one embodiment, glycerol monomethacrylate can be present at aconcentration of about 68% w/w of the final desiccated products and2-amino ethyl methacrylate can be present at a concentration of about 3%w/w of the final desiccated products.

In one embodiment, the one or more monomers can be 3-sulfopropylacrylate and amino propyl methacrylamide.

In one embodiment, 3-sulfopropyl acrylate can be present at aconcentration of about 59% w/w of the final desiccated products andamino propyl methacrylate can be present at a concentration of about 1%w/w of the final desiccated products.

A skilled artisan understands how to calculate final concentrationsbased on amount in solvent already discussed.

The polymerization of the macromer and optional one or more monomersusing free radical polymerization may require one or more initiators tostart the reaction. The polymerization solution can be polymerized byreduction-oxidation, radiation, heat, or any other method known in theart. Radiation polymerization of the prepolymer solution can be achievedwith ultraviolet light or visible light with suitable initiators orionizing radiation (e.g. electron beam or gamma ray) without initiators.Polymerization can be achieved by application of heat, either byconventionally heating the solution using a heat source such as aheating well, or by application of infrared light to the prepolymersolution. In one embodiment, the polymerization method utilizesazobisisobutyronitrile (AIBN) or another water soluble AIBN derivative(2,2′-azobis(2-methylpropionamidine) dihydrochloride). Other initiatorsuseful according to the present description includeN,N,N′,N′-tetramethylethylenediamine, ammonium persulfate, benzoylperoxides, and combinations thereof, including azobisisobutyronitriles.

In another embodiment, the initiator can be a combination ofN,N,N′,N′-tetramethylethylenediamine and ammonium persulfate at aconcentration of about 0.25% w/w and about 2% w/w, respectively. Inanother embodiment, an initiator includes a combination of about 1.5%ammonium persulfate and about 0.3% N,N,N′,N′-tetramethylethylenediamine.In still another embodiment, an initiator includes a combination ofabout 1.8% ammonium persulfate and about 0.2%N,N,N′,N′-tetramethylethylenediamine.

The polymerization solution can be prepared by dissolving the reactantssuch as combinations of monomer(s), macromers(s), multifunctionalcrosslinkers(s), and optionally initiator(s) in a solvent. The particleembolics can be prepared by emulsion polymerization. A non-solvent forthe monomer solution, typically mineral oil when the monomer solvent iswater, is sonicated to remove any entrapped oxygen. The mineral oil isadded to the reaction vessel. An overhead stirrer is placed in thereaction vessel. The reaction vessel is then sealed, degassed undervacuum, and sparged with an inert gas such as argon. The initiatorcomponent N,N,N′,N′-tetramethylethylenediamine is added to the reactionvessel and stirring commenced. Ammonium persulfate is added to thepolymerization solution and both are then added to the reaction vessel,where the stirring suspends droplets of the polymerization solution inthe mineral oil. A surfactant can be added before, after, or during theaddition of the polymerization solution to stabilize the suspension. Therate of stirring can affect particle size, with faster stirringproducing smaller particles. Stirring rates can be about 100 rpm, about200 rpm, about 300 rpm, about 400 rpm, about 500 rpm, about 600 rpm,about 700 rpm, about 800 rpm, about 900 rpm, about 1,000 rpm, about1,100 rpm, about 1,200 rpm, about 1,300 rpm, between about 200 rpm andabout 1,200 rpm, between about 400 rpm and about 1,000 rpm, at leastabout 100 rpm, at least about 200 rpm, at most about 250 rpm, at mostabout 500 rpm, at most about 1,000 rpm, at most about 1,300 rpm, or atmost about 1,200 rpm to produce particles with desired diameters.

Desired hydrated polymer particle diameters can be about 10 μm, about 20μm, about 30 μm, about 40 μm, about 50 μm, about 100 μm, about 200 μm,about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm,about 800 μm, about 900 μm, about 1,000 μm, about 1,100 μm, about 1,200μm, about 1,300 μm, about 1,400 μm, about 1,500 μm, about 1,600 μm,about 1,700 μm, about 1,800 μm, about 1,900 μm, about 2,000 μm, betweenabout 50 μm and about 1,500 μm, between about 100 μm and about 1,000 μm,at least about 50 μm, at least about 80 μm, less than about 600 μm, lessthan about 1,000 μm, less than about 1,200 μm, or less than about 1,500μm. In one embodiment, the diameter is less than about 1,200 μm.

Polymerization can be allowed to proceed as long as necessary to produceparticles with desired diameters. Polymerization can be allowed toproceed for about 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 5 hr, 6 hr, 7 hr, 8hr, 9 hr, 10 hr, 11 hr, 12 hr, 18 hr, 24 hr, 48 hr, 72 hr, 96 hr,between about 1 hr and about 12 hr, between about 1 hr and about 6 hr,between about 4 hr and about 12 hr, between about 6 hr and about 24 hr,between about 12 hr and about 72 hr, or at least about 6 hours.

Polymerization can be run at a temperature to produce particles withdesired diameters. Polymerization can be run at a temperature of about10° C., about 15° C., about 20° C., about 25° C., about 30° C., about35° C., about 40° C., about 45° C., about 50° C., about 60° C., about70° C., about 80° C., about 90° C., about 100° C., between about 10° C.and about 100° C., between about 10° C. and about 30° C., at least about20° C., at most about 100° C., or at about room temperature. In oneembodiment, polymerization occurs at room temperature.

After the polymerization is complete, the polymer particles can bewashed to remove any solute, mineral oil, un-reacted monomer(s), and/orunbound oligomers. Any solvent may be utilized and can include, but arenot limited to hexane, acetone, alcohols, water and a surfactant, water,organic solvents, saline, and combinations thereof. In one embodiment,the washing solution is water. In another embodiment, the washingsolution is a combination of hexane followed by water. In anotherembodiment, the washing solution is saline. In further embodiments, thewashing solution is water and a surfactant.

The particles described herein can optionally be loaded or coated with adrug(s) and/or active agent(s) including, but not limited toanti-proliferative compounds, cytostatic compounds, toxic compounds,anti-inflammatory compounds, chemotherapeutic agents, analgesics,antibiotics, protease inhibitors, statins, nucleic acids, polypeptides,growth factors and delivery vectors including recombinantmicro-organisms, liposomes, and the like. In one embodiment, particlescan be loaded with doxorubicin. In another embodiment, the particles canbe loaded with irinotecan. In still other embodiments, the particles canbe loaded with irinotecan and doxorubicin.

Drugs and/or active agents can be eluted from the particles onceimplanted. Elution can occur over about 1 hour, about 2 hours, about 5hours, about 10 hours, about 12 hours, about 18 hours, about 24 hours,about 2 days, about 3 days, about 4 days, about 5 days, about 7 days,about 2 weeks, about 1 month, about 2 months, about 6 months, about 9months, about 1 year, or about 2 years. For example, about 1 mg, about 2mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg, about30 mg, about 40 mg, or about 50 mg of drug or active agent can be elutedfrom the particles in a 22 hour or 24 hour period.

Optionally, the washed polymer particles can be dyed prior to, during,or after polymerization to permit visualization before injection into amicrocatheter. Any of the dyes from the family of reactive dyes whichbond covalently to the particle embolics can be used. Dyes can include,but are not limited to, reactive blue 21, reactive orange 78, reactiveyellow 15, reactive blue No. 19, reactive blue No. 4, C.I. reactive red11, C.I. reactive yellow 86, C.I. reactive blue 163, C.I. reactive red180, C.I. reactive black 5, C.I. reactive orange 78, C.I. reactiveyellow 15, C.I. reactive blue No. 19, C.I. reactive blue 21, any of thecolor additives. Some color additives are approved for use by the FDApart 73, subpart D. In other embodiments, a dye that can irreversiblybond to the polymer matrix of the particle embolic is utilized.

A dye bath can be made by dissolving sodium carbonate and the desireddye in water. Particle embolics are added to the dye bath and stirred.After the dying process, any unbound dye is removed through washing.After dying and washing, the particles can be packaged into vials orsyringes, and sterilized.

The particles described herein can be sterilized without substantiallydegrading the polymer. After sterilization, at least about 50%, about60%, about 70%, about 80%, about 90%, about 95% about 99% or about 100%of the polymer can remain intact. In one embodiment, the sterilizationmethod can be autoclaving and can be utilized before administration.

The final polymer particle preparation can be delivered to the site tobe embolized via a catheter, microcatheter, needle, or similar deliverydevice. A radiopaque contrast agent can be thoroughly mixed with theparticle preparation in a syringe and injected through a catheter untilblood flow is determined to be occluded from the site by interventionalimaging techniques.

The particles can remain substantially stable once injected. Forexample, the polymer particles can remain greater than about 60%, about70% about 80%, about 90%, about 95%, about 99% or about 100% intactafter about 5 days, about 2 weeks, about 1 month, about 2 months, about6 months, about 9 months, about a year, about 2 years, about 5 years,about 10 years, or about 20 years.

The polymer particles described herein can be compressible yet durableenough not to break apart or fragment. Substantially no change incircularity or diameter of particles may occur during delivery through amicrocatheter. In other words, after delivery through a microcatheter,the polymer particles described herein remain greater than about 60%,about 70% about 80%, about 90%, about 95%, about 99% or about 100%intact.

In one embodiment, particles before delivery through a microcatheter canhave an average diameter of 0.221±0.054 mm and a post-delivery diameterof 0.226±0.049 mm. These particles can also exhibit a pre-deliveryaverage formcircle of 0.98±0.04 and a post-delivery formcircle of0.98±0.02.

In another embodiment, particles before delivery through a microcathetercan have an average diameter of 395±25 μm and a post-delivery diameterof 401±30 μm. These particles can also exhibit a pre-delivery averageformcircle of 0.98±0.01 and a post-delivery formcircle of 0.98±0.04.

Further, the particles can be cohesive enough to stick to tissue and/orremain in place through friction with the tissue. In other embodiments,the particles can act as a plug in a vessel held in place by the flowand pressure of blood.

In one example embodiment, a polymer particle can include a reactionproduct of a polyether, glycerol monomethacrylate, bisacrylamide, andaminoethyl methacrylate. In another example embodiment, a desiccatedpolymer particle can include a polyether at about 28% w/w, glycerolmonomethacrylate at about 68% w/w, bisacrylamide at about 1% w/w, andaminoethyl methacrylate at about 3% w/w.

On another example embodiment, a desiccated polymer particle can includea reaction product of a polyether, aminopropyl methacrylamide, andsulfopropyl acrylate. In another embodiment, a polymer particle caninclude a polyether at about 40%, aminopropyl methacrylamide at about1%, and sulfopropyl acrylate at about 59%.

Example 1 Preparation of a Polyether Macromer

Polyethylene glycol 10,000 (450 g) was dried by azeotropic distillationwith 2,400 mL of toluene. Then, 200 mL of dichloromethane, 15.6 mL oftriethylamine, and 10.4 mL of mesyl chloride were added and the solutionwas stirred for 4 hr. The solution was filtered, the productprecipitated in diethyl ether, and collected by filtration. Theresulting product was vacuum dried, added to 3,600 mL of 25% of ammoniumhydroxide, and stirred closed for 4 days then open for 3 days. The waterwas removed and the product dried by azeotropic distillation withtoluene. To the resulting poly(ethylene glycol) diamine in toluene, 15.6mL of triethylamine and 10.9 mL of acryloyl chloride were added and thereaction was stirred for 4 hr. The resulting solution was filtered,precipitated in ether and the solvent removed, yielding PEG 10,000diacrylamide.

Example 2 Particle Embolic Prepared with a Polyether Macromer and aPlurality of Monomers

The prepolymer formulation is prepared by dissolving 0.25 g 2-aminoethylmethacrylate, 2.125 g poly(ethylene glycol) diacrylamide from Example 1,5.1 g glycerol monomethacrylate, 0.07 g N,N′-methylenebisacrylamide, and1.2 g sodium chloride in 20 mL of de-ionized water. The solution wasfiltered into a clean 120 mL amber jar. An initiator solution was madeby dissolving 1.0 g ammonium persulfate in 2.0 g of de-ionized water.Then, 1.0 mL of the ammonium persulfate solution was added to thefiltered prepolymer solution, and the solution was vacuum degassed for 2min, and the vacuum was replaced with argon. 500 mL of mineral oil weresonicated for 1 hr, and then added to a sealed reaction vessel with anoverhead stirring element. The vessel was vacuum degassed for 1 hr, andthen the vacuum replaced with argon. Then, 1 mL ofN,N,N′,N′-tetramethylethylenediamine was added to the reaction vesseland overhead stirring started at 200 rpm. The prepolymer formulation wasadded to the reaction vessel. After 1 min, 0.1 mL of SPAN® 80 (sorbitanmonooleate, Croda International Plc, East Yorkshire, purchased fromSigma-Aldrich Company LLC, St. Louis, Mo.) was added and the preparationwas allowed to polymerize for at least 2 hr. The oil was decanted offand the particles were poured into a separatory funnel with 1,000 mL ofde-ionized water. The bottom water/sphere layer was collected. Theparticles were washed with several 300 mL portions of hexane. After thefinal wash, all hexane was decanted off and the particles were washedseveral times with fresh 300 mL portions of de-ionized water and storedin a capped bottle with de-ionized water.

Example 3 Particle Embolic Prepared with a Polyether Macromer

A prepolymer formulation was prepared by dissolving 15.8 g poly(ethyleneglycol) diacrylamide and 6.0 g of sodium chloride in 30.0 g ofde-ionized water. Then, 10 g of this solution was filtered. An initiatorsolution was made by dissolving 1.0 g ammonium persulfate in 2.0 gramsof de-ionized water. The ammonium persulfate solution (1 mL) was addedto the filtered prepolymer solution, the solution was vacuum degassedfor 2 min, and the vacuum was replaced with argon. Then, 500 mL ofmineral oil was sonicated for 2 hr, and then added to a sealed reactionvessel with 0.5 mL of SPAN® 80 and an overhead stirring element. Thevessel was vacuum degassed for 1 hr, and then the vacuum replaced withargon. Then, 1 mL of N,N,N′,N′-tetramethylethylenediamine was added tothe reaction vessel and overhead stirring started at 450 rpm. The 10 gof prepolymer formulation was added to the reaction vessel via syringeand allowed to polymerize for at least 8 hr.

Example 4 Particle Embolic Prepared with a Polyether Macromer andMonomer

A prepolymer formulation was prepared by dissolving 9.2 g poly(ethyleneglycol) diacrylamide from Example 1, 13.8 g 3-sulfopropyl acrylatepotassium salt, and 0.248 g n-(3-aminopropyl)methacrylamidehydrochloride in 34.4 g of deionized water. Then, the solution wasfiltered. An initiator solution was made by dissolving 1.0 g ammoniumpersulfate in 2.0 g of deionized water. Ammonium persulfate solution(0.85 mL) was added to the filtered prepolymer solution, the solutionwas then vacuum degassed for 2 min, and added to a sealed reactionvessel with 0.14 mL of SPAN® 80 and an overhead stirring element. Thevessel was vacuum degassed for 1 hr, and then the vacuum was replacedwith argon. N,N,N′N′-tetramethylethylenediamine (2 mL) was added to thereaction vessel and overhead stirring started at 400 rpm. The prepolymerformulation was added to the reaction vessel via syringe and allowed topolymerize for at least 8 hr.

Example 5 Purification of Particle Embolics

The mineral oil was decanted from the reaction vessel, and the polymerparticles were washed three times with fresh portions of hexane toremove the mineral oil. The particles were then transferred to aseparatory funnel with water, and separated from residual mineral oiland hexane. Next, the particles are washed with de-ionized water toremove any residual reactants. The particles can be packaged in 0.9%saline solution for the final preparation or dyed.

Example 6 Dying of Particle Embolics

To dye the particles, 50 g of sodium carbonate and 0.1 g reactive black5 dye (Sigma-Aldrich Co. LLC, St. Louis, Mo.) were dissolved in 1,000 mLof de-ionized water. Then, 500 mL of drained particles were added andallowed to stir for 1 hr. The dyed particle preparation was washed withde-ionized water until all residual dye was removed. The particles canthen be packaged in 0.9% saline solution for the final preparation.

Example 7 Drug Loading Particle Embolics

Particles prepared in Example 4 were sieved to 100-300 μm and loadedwith the drug doxorubicin. Four 1 mL particle aliquots were loaded with37.5 mg of doxorubicin in solution. The solution was analyzed by anAgilent 1100 HPLC system before and after adding particles to determineamount of drug sequestered by the particles from the solution.

Loading particles with doxorubicin: 37.5 mg of doxorubicin was dissolvedin 2 mL of de-ionized water. A drop of the drug solution was saved forLC analysis. The saline storage fluid was removed from a 1 mL vial ofparticles and the drug solution added to the vial of particles. After 18hours, a sample of the solution was analyzed, and the drug loading wasdetermined by comparing peak area of drug present in solution before andafter adding particles.

Particles prepared in Example 4 were similarly loaded with the drugirinotecan. Four 1 mL aliquots of particles sized 100-300 μm were loadedwith 50.0 mg of irinotecan dissolved in citrate buffer solution. Thesolution was analyzed before and after adding particles.

Loading particles with irinotecan: 50.0 mg of irinotecan was dissolvedin 5 mL of pH 4 citrate buffer solution. A drop of the solution wassaved for LC analysis. The saline storage solution was removed from a 1mL vial of particles and the irinotecan solution was added. After 18 hra sample of the solution was analyzed and the drug loaded determined bycomparing the peak area of drug present in solution before and afteradding particles (FIG. 1).

Example 8 Drug Elution of Particle Embolic

Particles prepared in example 4 were aliquoted into six 1 mL samples andloaded with drug per Example 7. Excess drug solution was removed fromthe sample of particles after an 18 hr incubation period. The sampleswere placed into the dissolution chambers of a Sotax CE7 Smart USP 4dissolution apparatus. The elution media of saline solution was run at37.5° C. for 22 hours with samples taken at various time points. Thesamples were analyzed by an Agilent 1100 HPLC system and milligrams ofdrug eluted calculated. Results are illustrated in FIG. 2.

Example 9 Compressive Modulus of Particle Embolic

Particles created as described herein are often delivered through acatheter with a smaller inner lumen than the average outer diameter ofthe particles. The compressive modulus required to compress a sample ofparticles to 30% of their a nominal diameter was tested on a Instron5543 materials testing machine equipped with a 5 N load cell. To test asample, an approximately 1 cm circular monolayer of spherical particlesstored in saline, nominally sized 800 μm diameter, was placed on a flatlower platen. Excess saline was carefully blotted away with a lab wipe.A flat probe compressed the beads to 30% of the beads' average diameterand the Young's modulus was recorded. The test was repeated 3-5 timesfor each sample.

Two samples of spherical particles nominally sized 800 μm diameter fromExample 2 and Example 3 were tested as described previously and theresults are illustrated in FIG. 3.

Two 1 mL aliquots of spherical particles nominally sized 800 μm fromExample 4 were loaded with irinotecan and doxorubicin per Example 7. Thecompressibility was measured before and after loading with drug and theresults are illustrated in FIG. 4.

Example 10 Determination of Suspension Properties of Particles inRadiopaque Contrast

Particle embolics can be prepared for delivery in radiopaque contrastsolution. A homogeneous mixture of particles suspended in contrastsolution can permit a uniform injection of beads through a catheter. Totest suspension characteristics of embolic particles, a 10 mL syringewith 1 mL of particles and 2 mL of buffered saline were attached to a3-way stopcock. Another syringe containing 3 mL of OMNIPAQUE® 300(iohexol formulated as 300 mg of iodine per mL, GE Healthcare, Norway)contrast was attached to the stopcock. The contrast was injected intothe particle syringe and a timer was started. The syringe containingcontrast, saline, and particles was removed from the stopcock and cappedwith a syringe tip cap. The contents were mixed by inverting the syringerepeatedly. At a time point, the mixing was stopped and a second timerstarted. The time taken for particles to remain only in ⅔ of the syringewas recorded. Mixing by inverting was continued between measurements.

Particles from Example 2 and Example 3, nominally sized 800 μm diameterwere tested using the method described above and results are illustratedin FIG. 5.

Particles from Example 4, nominally sized 400 μm and drug loaded withdoxorubicin were tested for suspension characteristics. To do so, 1 mLof the drug loaded particles and the solution they were drug loaded inwere placed in a 10 mL syringe. Excess drug solution was expressed fromthe syringe and the syringe was attached to a 3-way stop cock. A second10 mL syringe containing OMNIPAQUE® 300 contrast was attached to the3-way stopcock. Enough contrast solution was added to the syringecontaining the particles to make a total volume of 6 mL and the timerwas started. The syringe containing contrast and particles was removedfrom the stopcock and capped with a syringe tip cap. The contents weremixed by inverting the syringe repeatedly. At a time point, the mixingwas stopped and a second timer started. The time taken for particles toremain only in ⅔ of the syringe was recorded. Mixing by inverting wascontinued between measurements.

Particles from Example 4, nominally sized 400 μm and drug loaded withirinotecan were tested for suspension characteristics. To do so, 1 mL ofthe drug loaded particles and drug loading solution were placed in a 10mL syringe. Excess drug solution was expressed from the syringe and thesyringe was attached to a 3-way stopcock. A second 10 mL syringecontaining de-ionized water was attached to the 3-way stopcock and waterwas injected into the syringe containing the drug loaded particles tobring the total volume to 3 mL. The syringe containing water was removedand a syringe containing OMNIPAQUE® 300 contrast was attached to the3-way stopcock. Enough contrast solution was added to the syringecontaining the particles to make a total volume of 6 mL and the timerwas started. The syringe containing contrast and particles was removedfrom the stopcock and capped with a syringe tip cap. The contents weremixed by inverting the syringe repeatedly. At various time points, themixing was stopped and a second timer started. The time taken forparticles to remain only in ⅔ of the syringe was recorded. Mixing byinverting was continued between measurements.

Results for particles loaded with doxorubicin and irinotecan areillustrated in FIG. 6.

Example 11 Determination of Durability of Particle Embolics afterCatheter Delivery

To simulate use, a 1 mL sample of particles prepared in Example 3 wasinjected through a Headway 21 catheter (0.021″, 533 μm inner lumen). Onemilliliter of particles with 2 mL of saline in a syringe were attachedto a 3-way stopcock. The catheter and a syringe containing 3 mL ofOMNIPAQUE® 300 contrast solution were also attached to the 3-waystopcock. The stopcock was opened between the syringes to mix the beads,saline, and contrast. This particle preparation was then contained inone syringe, the other syringe removed, and a 1 mL injection syringeattached to the stopcock in line with the catheter. The particles weredelivered through the catheter into a dish. An image was acquired usinga Zeiss Axio Imager A1 microscope and analyzed using Zeiss Axiovisionimage analysis software. The circularity (closeness to a circle) wasscored and statistical analysis using a Student's t-test indicated nodifference in the spherical particles before and after delivery, with nodamaged spheres observed.

Pre-Delivery Table Diameter Sphere # Formcircle (μm) 1 0.93 481 2 0.97372 3 0.97 411 4 0.97 390 5 0.97 373 6 0.97 407 7 0.97 405 8 0.97 388 90.98 412 10 0.98 393 11 0.98 414 12 0.98 388 13 0.98 386 14 0.98 360 150.98 433 16 0.98 380 17 0.98 414 18 0.98 404 19 0.98 361 20 0.98 385 210.98 376 22 0.98 387 23 0.98 373 24 0.98 376 25 0.98 396 26 0.98 443 270.98 380 28 0.98 380 29 0.99 412 30 0.99 381

Post-Delivery Table Diameter Sphere # Formcircle (μm) 1 0.7 564 2 0.83432 3 0.85 458 4 0.91 455 5 0.92 411 6 0.93 375 7 0.94 475 8 0.95 463 90.96 414 10 0.97 391 11 0.97 388 12 0.97 391 13 0.97 397 14 0.97 376 150.98 395 16 0.98 378 17 0.98 400 18 0.98 359 19 0.98 380 20 0.98 381 210.98 416 22 0.98 412 23 0.98 410 24 0.98 418 25 0.98 382 26 0.98 404 270.98 409 28 0.98 411 29 0.98 387 30 0.98 376 31 0.98 416 32 0.98 426 330.99 392 34 0.99 424 35 0.99 388 36 0.99 390 37 0.99 390 38 0.99 391 390.99 385 40 0.99 386 41 0.99 417 42 0.99 411 43 0.99 398 44 0.99 439 450.99 419 46 0.99 386 47 0.99 418 48 0.99 368 49 0.99 420 50 0.99 375 510.99 391 52 0.99 392 53 0.99 418 54 0.99 384 55 0.99 369 56 0.99 396 570.99 408 58 1 399 59 1 387 60 1 395 61 1 391 62 1 388 63 1 391 64 1 37065 1 409 66 1 364 67 1 392 68 1 364 69 1 415 70 1 371 71 1 423 72 1 38073 1 406 74 1 428 75 1 364 76 1 367 77 1 371 78 1 381 79 1 384 80 1 38981 1 408

Summary Table Average Diameter Pre-delivery, μm 395 ± 25  AverageDiameter Post-delivery, μm 401 ± 30  Average Formcircle Pre-delivery0.98 ± 0.01 Average Formcircle Post-delivery 0.98 ± 0.04

Example 12 Determination of Durability of Drug Loaded Particle Embolicsafter Delivery

To simulate use of a drug loaded particle embolic, 1 mL sample ofparticles prepared in Example 4 was injected through a Headway 17catheter (0.017″, 432 μm inner lumen). Then, a syringe charged with 1 mLof particles loaded with doxorubicin per example 7 with 2 mL ofde-ionized water was attached to a 3-way stopcock. The catheter and asyringe containing 3 mL of OMNIPAQUE® 300 radiopaque contrast solutionwere also attached to the 3-way stopcock. The stopcock was openedbetween the syringes to mix the beads, saline, and contrast. Thisparticle preparation was then contained in one syringe, the othersyringe removed, and a 1 mL injection syringe attached to the stopcockin line with the catheter. The particles were delivered through thecatheter into a dish. An image was acquired using a Zeiss Axio Imager A1microscope and analyzed using Zeiss Axiovision image analysis software.The circularity (closeness to circle) was scored and statisticalanalysis using a Student's t-test indicated no difference in thespherical particles before and after delivery, with no damaged spheresobserved.

Pre-Delivery Table Diameter Sphere # Formcircle (mm) 1 0.73 0.173 2 0.950.148 3 0.95 0.266 4 0.96 0.265 5 0.96 0.203 6 0.96 0.159 7 0.97 0.221 80.97 0.263 9 0.97 0.176 10 0.98 0.305 11 0.98 0.2 12 0.98 0.172 13 0.980.193 14 0.98 0.237 15 0.98 0.226 16 0.98 0.202 17 0.98 0.277 18 0.980.203 19 0.98 0.288 20 0.99 0.167 21 0.99 0.213 22 0.99 0.176 23 0.990.203 24 0.99 0.301 25 0.99 0.27 26 0.99 0.199 27 0.99 0.247 28 0.990.208 29 0.99 0.212 30 0.99 0.391 31 0.99 0.201 32 0.99 0.177 33 0.990.175 34 0.99 0.158 35 1 0.243 36 1 0.198 37 1 0.299 38 1 0.147 39 10.19 40 1 0.189 41 1 0.324

Post-Delivery Table Diameter Sphere # Formcircle (mm) 1 0.89 0.252 20.93 0.211 3 0.94 0.176 4 0.94 0.26 5 0.95 0.208 6 0.95 0.298 7 0.950.23 8 0.96 0.233 9 0.96 0.186 10 0.97 0.274 11 0.97 0.142 12 0.97 0.30213 0.97 0.211 14 0.97 0.247 15 0.97 0.271 16 0.97 0.236 17 0.97 0.173 180.97 0.267 19 0.98 0.266 20 0.98 0.233 21 0.98 0.214 22 0.98 0.174 230.98 0.244 24 0.98 0.212 25 0.98 0.273 26 0.98 0.288 27 0.98 0.275 280.98 0.258 29 0.98 0.27 30 0.98 0.191 31 0.98 0.191 32 0.98 0.214 330.98 0.26 34 0.98 0.173 35 0.98 0.224 36 0.98 0.13 37 0.98 0.266 38 0.980.34 39 0.98 0.221 40 0.98 0.134 41 0.99 0.212 42 0.99 0.291 43 0.990.298 44 0.99 0.206 45 0.99 0.315 46 0.99 0.242 47 0.99 0.198 48 0.990.3 49 0.99 0.26 50 0.99 0.187 51 0.99 0.132 52 0.99 0.199 53 0.99 0.16854 0.99 0.274 55 0.99 0.186 56 0.99 0.279 57 0.99 0.22 58 0.99 0.232 590.99 0.247 60 0.99 0.162 61 0.99 0.178 62 0.99 0.209 63 1 0.147 64 10.156 65 1 0.185 66 1 0.204

Summary Table Average Diameter Pre-delivery, mm 0.221 ± 0.054 AverageDiameter Post-delivery, mm 0.226 ± 0.049 Average Formcircle Pre-delivery0.98 ± 0.04 Average Formcircle Post-delivery 0.98 ± 0.02

Example 13 Polymer Microsphere Comprised of a Macromer and Plurality ofMonomers, Diluted Prepolymer Solution

The prepolymer formulation was prepared by dissolving 0.35 g2-aminoethyl methacrylate, 2.98 g poly(ethylene glycol) diacrylamidefrom Example 1, 7.16 g glycerol monomethacrylate, 0.098 gN,N′-methylenebisacrylamide, and 3.0 g sodium chloride in 40 mL ofde-ionized water. The solution was filtered into a clean 120 mL amberjar. An initiator solution was made by dissolving 1.0 g ammoniumpersulfate in 2.0 g of de-ionized water. 1.0 mL of the ammoniumpersulfate solution was added to the filtered prepolymer solution, andthe solution was vacuum degassed for 2 min, and the vacuum was replacedwith argon. Then, 500 mL of mineral oil were sonicated for 1 hr, andthen added to a sealed reaction vessel with an overhead stirringelement. The vessel was vacuum degassed for 1 hr, and then the vacuumreplaced with argon. Then, 1 mL of N,N,N′,N′-tetramethylethylenediaminewas added to the reaction vessel and overhead stirring started at 200rpm. The prepolymer formulation was added to the reaction vessel. After1 min, 0.1 mL of SPAN® 80 was added and the preparation was allowed topolymerize for at least 2 hr. The oil was decanted off and the particleswere poured into a separatory funnel with 1,000 mL of de-ionized water.The bottom water/sphere layer was collected. The particles were washedwith several 300 mL portions of hexane. After the final wash, all hexanewas decanted off and the particles were washed several times with fresh300 mL portions of de-ionized water and stored in a capped bottle withde-ionized water.

Example 14 Particle Embolic Prepared with a Polyether Macromer andMonomer

A prepolymer formulation was prepared by dissolving 10.0 g poly(ethyleneglycol) diacrylamide from Example 1, and 15.0 g 3-sulfopropyl acrylatepotassium salt, in 35.0 g of de-ionized water. Then, 55 g of thissolution was filtered. An initiator solution was made by dissolving 1.0g ammonium persulfate in 2.0 g of deionized water. Ammonium persulfatesolution (1 mL) was added to the filtered prepolymer solution, thesolution was then vacuum degassed for 2 min, and the vacuum was replacedwith argon. Then, 1000 mL of mineral oil was sonicated for 2 hr, andthen added to a sealed reaction vessel with 0.5 mL of SPAN® 80 and anoverhead stirring element. The vessel was vacuum degassed for 1 hr, andthen the vacuum was replaced with argon.N,N,N′,N′-tetramethylethylenediamine (1 mL) was added to the reactionvessel and overhead stirring started at 450 rpm. The prepolymerformulation (55 g) was added to the reaction vessel via syringe, then0.35 mL of SPAN® 80. The beads were allowed to polymerize for at least 8hr.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the devices, techniquesand methods disclosed herein elucidate representative embodiments thatfunction well in the practice of the present disclosure. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects those of ordinary skill in the art toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A polymer particle comprising: a poly(ethylene glycol)diacrylamide macromer, a first monomer; and a second monomer selectedfrom acrylic acid, methacrylic acid, 3-sulfopropyl acrylate,3-sulfopropyl methacrylate, a salt thereof, or a combination thereof. 2.The polymer particle of claim 1, wherein the polymer particle has adiameter between about 40 μm and about 1,200 μm.
 3. The polymer particleof claim 1, wherein the polymer particle has a diameter less than about1,200 μm.
 4. The polymer particle of claim 1, wherein the first monomerincludes a functional group.
 5. The polymer particle of claim 4, whereinthe functional group is an acrylate, an acrylamide, a methacrylate, or amethacrylamide.
 6. The polymer particle of claim 1, wherein the firstmonomer is glycerol monomethacrylate, amino ethyl methacrylate, aminopropyl methacrylate, or a combination thereof.
 7. The polymer particleof claim 1, wherein the polymer particle is spherical.
 8. The polymerparticle of claim 1, wherein the poly(ethylene glycol) diacrylamide ispoly(ethylene glycol) diacrylamide 10,000.
 9. The polymer particle ofclaim 1, wherein the poly(ethylene glycol) macromer is at aconcentration of about 28% w/w.
 10. A polymer particle comprising: apoly(ethylene glycol) diacrylamide macromer, a first monomer; and asecond monomer selected from amino ethyl methacrylate, 2-amino ethylmethacrylate, amino propyl methacrylamide, a salt thereof, or acombination thereof.
 11. The polymer particle of claim 10, wherein thepolymer particle has a diameter between about 40 μm and about 1,200 μm.12. The polymer particle of claim 10, wherein the polymer particle has adiameter less than about 1,200 μm.
 13. The polymer particle of claim 10,wherein the first monomer includes a functional group.
 14. The polymerparticle of claim 13, wherein the functional group is an acrylate, anacrylamide, a methacrylate, or a methacrylamide.
 15. The polymerparticle of claim 10, wherein the first monomer is glycerolmonomethacrylate, 3-sulfopropyl acrylate, or a combination thereof. 16.The polymer particle of claim 10, wherein the polymer particle isspherical.
 17. The polymer particle of claim 10, wherein thepoly(ethylene glycol) diacrylamide is poly(ethylene glycol) diacrylamide10,000.
 18. The polymer particle of claim 10, wherein the poly(ethyleneglycol) macromer is at a concentration of about 28% w/w.
 19. A kit,comprising the polymer particle of claim
 1. 20. A kit, comprising thepolymer particle of claim
 10. 21. A polymer particle, comprising: apoly(ethylene glycol) diacrylamide macromer at a concentration ofbetween about 15% w/w and about 50% w/w; and at least one monomer thatis not n-isopropyl acrylamide.
 22. An embolic, comprising a plurality ofthe polymer particle of one of claims 1-21.